1. Field
The present disclosure relates to boron-based prodrugs, methods for making the same, methods for increased bioavailability and lowered dosage requirements for drug molecules that contain one or more phenol groups, and the synthesis and use of the same. Further, the present disclosure teaches the utilization of said prodrugs as improved medications with lower-dose and longer-lasting efficacy.
Use of the boron-based prodrugs as improved medications can be particularly beneficial in reducing detrimental side effects and unintentional overdose by using significantly lower doses to achieve the same therapeutic effect as the unmodified drug. Furthermore, the prodrugs described herein afford improved pharmacokinetic properties with longer half-life in plasma, making it possible to reduce the frequency of medication.
2. Description of Related Art
Many active drug molecules contain one or more substituted or unsubstituted phenolic groups, or aromatic hydroxyl groups, and are amenable to the described boron-based modification towards desired prodrugs for enhancement in bioavailability and bio-retention and, in particular, significantly lower the therapeutically effective dosage to reduce adverse effects. Any active drug molecule containing one or more hydroxyl groups as described above can be chemically modified to any of the boronic prodrugs using methods taught in the present disclosure.
Fulvestrant
Fulvestrant is a selective estrogen receptor downregulator (SERD) that was approved by FDA in 2003 as treatment for breast cancer following failure on Tamoxifen and/or aromatase inhibitors (AI). Fulvestrant is a pure anti-estrogen with no known agonist effects. Clinically it has been shown to be as effective as anastrozole when used to treat patients who had recurrence or relapse after Tamoxifen or AI treatment. Due to its poor oral bioavailability, the drug is currently administered by intramuscular (IM) injection at the approved dose of 250 mg (Croxtall et al. Drugs. 2011; 71(3):363-80). Further pharmacological and pre-clinical studies suggest that a higher dose of 500 mg may be more effective and clinical trials have been conducted to test the benefits of administering fulvestrant at a higher dose (Stevez et al. Cancer Treat Rev. 2013; 39(2):136-41). The data highlight the need to improve bioavailability to make fulvestrant a more effective therapeutic regimen for Tamoxifen-resistant breast cancer.
Acetaminophen
Tylenol is one of the most popular over the counter analgesics (pain killer) and antipyretics (fever reducer) in the United States, making up about 35% of the pain killer market in North America (Lee, NEJM. 2003; 349:474-485). Americans take over 8 billion pills (tablets or capsules) of Tylenol each year for treatment of pain symptoms and fever. Acetaminophen is also a common active ingredient present in as many as 600 different over the counter drugs according to a statement issued by the pharmaceutical company Johnson and Johnson. For example, Anacin-3, Liquiprin, Panadol, and various cold and flu medicines all contain acetaminophen. Acetaminophen overdose is currently the most frequent cause of acute liver failure in USA, the UK and many other countries (Larson et al. Hepatology. 42:1364-1372, 2005). Each year, acetaminophen-associated overdoses account for about 56,000 emergency room visits and 26,000 hospitalizations (Nourjah et al. Pharmacoepidemiol Drug Saf. 2006; 15(6):398-405). In 2001, nearly 50% of all acetaminophen exposures reported were unintentional in nature and more than 50% were treated in a healthcare facility. Overall, acetaminophen-associated fatalities represented 16% of the total 1074 fatalities that were reported in TESS in 2001. Approximately 50% of acetaminophen-associated fatalities occurred in individuals who took single-ingredient acetaminophen products which are available as OTC drugs. Beginning in October 2013, in an effort by Tylenol's parent company, Johnson & Johnson, to reduce the number of accidental acetaminophen overdoses that occur each year, bottles of Extra Strength Tylenol would carry a new warning on the caps: “Contains acetaminophen. Always read the label.” This latest move by Johnson & Johnson underscores the continued need to reduce acetaminophen overdose and prevent liver failure and loss of life.
Raloxifene
Raloxifene was approved in 2007 by the U.S. Food and Drug Administration for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer. Raloxifene is available in 60 mg tablets taken daily. Common adverse effects include hot flashes and leg cramps. Raloxifene may infrequently cause serious blood clots to form in the legs, lungs, or eyes. Other reactions experienced include leg swelling/pain, trouble breathing, chest pain, vision changes. Raloxifene can also cause developmental abnormalities such as birth defects. The relatively high dosage requirement of raloxifen (for example, compared to 20 mg/day for Tamoxifen and 1 mg/day for anastrozole) is due to its poor bioavailability (Kemp et al. Drug Metab Dispos. 2002; 30:694-700; Jeong et al. Drug Metab Dispos. 2005; 33:785-94).
Irinotecan (SN-38)
Irinotecan is hydrolysed by carboxylesterases into its active metabolite SN-38 (Garcia-Carbonero et al. Clin Cancer Res. 2002; 8(3):641-61). Use of boron-SN-38 ensures the desired concentration level of SN-38 without relying on metabolic conversion of irinotecan. Moreover, boron-SN-38 is preferentially enriched in plasma and in tumor loci, thus requiring significantly lower dosage to achieve the same therapeutic effects as treated by irinotecan at several-fold higher dosage. Such lowered dosage requirement in turn will reduce cytotoxicities of the drug to healthy tissues and organs.
Niclosamide
Niclosamide has been shown to inhibit the spread of colon cancer in animal studies. The drug works by blocking the expression of gene called S100A4/metastasin, which can prompt colon cancer metastasis. However, niclosamide has poor water solubility and low oral bioavailability (Navab et al. J. Lipid Res. 2009; 50:1538-1547), thereby limiting its clinical development as a cancer treatment regimen.
The solution to this technical problem is provided by the embodiments characterized in the claims.